Porphyria COPY Flashcards
1
Q
definition of porphyrias
A
- a group of metabolic disorders resulting from a mutation in one of the enzymes in the heme biosynthetic pathway
2
Q
what are porphyrins
A
- the toxic metabolites produced from the heme biochemical pathway
3
Q
can porphyrins be cleared?
A
- no
4
Q
why can porphyrins not be cleared?
A
- due to deficient enzyme action
5
Q
function of porphyrins
A
- no useful function
- act as highly reactive oxidants and damage tissues
6
Q
heme is a part of
A
- hemoglobin
- myglobin
- catalase
- peroxidases
- cytochromes
7
Q
where is heme made?
A
- 85% in erythroid cells
- rest in liver
8
Q
what is heme used to make
A
- P450 enzymes
9
Q
first enzyme in heme synthesis pathway
A
- ALA synthetase (ALAS)
10
Q
importance of ALAS
A
- first and rate limiting enzyme
11
Q
what induces ALAS
A
- increased demand for heme
12
Q
what down regulates ALAS
A
- the heme molecule
- by feedback inhibition
13
Q
role of ALAS
A
- catalyzes conversion of glycine and succinyl CoA
- forms delta-aminolevulinic acid
14
Q
co-factor required by ALAS
A
- pyridoxal-5-phosphate
15
Q
things that induces ALAS
A
- depletion of hepatic pool of heme
- drugs, hormones that induce CYPs and ALAS1
- caloric and carbohydrate restriction
- metabolic stress
16
Q
role of metabolic stress in inducing ALAS
A
- may induce heme oxygenase and accelerate heme destruction
17
Q
commonality of acute intermittent porphyria
A
- most common acute porphyria
18
Q
acute intermittent porphyria due to deficiency in
A
- hepatic PBG deaminase
- hydroxymethylbilane synthase
19
Q
acute intermittent porphyria genetic pattern
A
- autosomal dominant
- incomplete (low) penetrance
20
Q
acute intermittent porphyria - effect on erythrocyte PBG deaminase activity in affected individuals
A
- 50% reduction
21
Q
acute intermittent porphyria - when does it appear
A
- latent prior to puberty
22
Q
acute intermittent porphyria - in males or females?
A
- symptoms more common in females
23
Q
acute intermittent porphyria - what levels are increased during crisis?
A
- urinary ALA
- PBG
24
Q
reaction that PBG deaminase catalyzes
A
- PBG -> hydroxymethylbilane
25
acute intermittent porphyria - what is primarily increased by environmental and other factors that increase disease severity
- ALAS1
26
does acute intermittent porphyria always develop in all individuals with the mutation?
- no
27
enzyme levels in acute intermittent porphyria
- low PBGD activity
| - induction of ALAS1
28
GI symptoms of acute intermittent porphyria acute attack
- abdominal pain
| - no inflammatory signs
29
most common feature of acute intermittent porphyria acute attack
- abdominal pain
30
no inflammatory signs means
- no elevated WBC
- no fever
- no rebound tenderness
31
peripheral neuropathy symptoms of acute intermittent porphyria
- sensory and motor neuropathy
| - may precede abdominal pain
32
acute intermittent porphyria- motor peripheral neuropathy in prolonged attacks
- involve cranial nerves
| - lead to bulbar paralysis, respiratory impairment, death
33
acute intermittent porphyria - autonomic nervous system features
- elevated catecholamines
34
acute intermittent porphyria - elevated catechomaines cause
- elevated heart rate
| - elevated blood pressure
35
acute intermittent porphyria - neuropsychiatric findings
- insomnia
36
acute intermittent porphyria - CNS involvement
- seizures
37
acute intermittent porphyria - hypothalamus features
- SAIDH
| - hyponatremia
38
what is hyponatremia?
- low sodium
39
acute intermittent porphyria - GU symptoms
- dark or reddish brown urine
40
acute intermittent porphyria - abnormal color of urine due to
- accumulation of porphyrins or porphyrin precursors
41
abnormal urine color between attacks
- may lessen or return to normal
42
acute intermittent porphyria - exacerbating factors of an acute attack
- drugs
- crash diets
- endogenous hormones
- cigarette smoking
- metabolic stresses
43
acute intermittent porphyria - exacerbating factors of acute attack - which drugs?
- drugs that increase demand for hepatic heme
| - cytochrome P450 enzymes
44
acute intermittent porphyria - crash diets
- decreased carb intake
45
acute intermittent porphyria - endogenous hormones
- progesterone
46
acute intermittent porphyria - cigarette smoking
- induces cytochrome P450
47
acute intermittent porphyria metabolic stresses
- infections, surgery, psychological stress
48
acute intermittent porphyria - making the diagnosis
- send urine for PBG and ALA during acute exacerbation
49
if PBG and ALA during acute exacerbation are not elevated
- then stop
50
if PBG and ALA are markedly elevated
- send PBG deaminase activity
51
acute intermittent porphyria - treatment of acute attack
- hospitalization
- withdraw unsafe meds
- IV 10% glucose
- IV hematin ASAP
52
how much 10% IV glucose do you give?
- 300 g per day
53
what do you give for treatment of crisis and prevention of attacks?
- Cimetidine
54
mechanism of action of hematin
- reduces production of ALA/porphyrins by negative feedback inhibition on ALA synthase
55
adverse reactions with hematin due to
- degradation products binding to endothelial cells, platelets, and coagulation factors
56
adverse reactions of hematin
- thrombophlebitis
- anticoagulation (inc PT)
- thrombocytopenia
- iron overload with repeated use
57
porphyria cutanea tarda caused by
- deficiency of UROD (uroporphyrinogen decarboxylase)
58
60% of PCT patients
- male
| - drink alcohol
59
women who develop PCT
- often on estrogen containing meds
60
age of most patients with PCT
- over 40
61
66% of patients with PCT have evidence of
- iron overload
62
reaction catalyzed by UROD
- uroporphrinogen lII -> coproprophyrinogen III
63
pathogenesis of PCT
- iron overload leads to reduced activity of UROD enzyme
| - leads to elevated uroporphyrin levels
64
what levels are correlated with PCT
- hepatic iron levels
65
PCT association with up regulation of ALAS1 synthase
- does not appear to be associated with
66
associated disorders with PCT
- alcoholism
- hemochromatosis
- hepatitis C
67
skin findings of PCT
- blisters
- bullae
- hyper and hypopigmentation
- also hirsutism
ON SUN EXPOSED AREAS OF THE BODY
68
bullae contains
- porphyrin rich serious or sersanguinous fluid
| - may be painful or become infected
69
PCT liver enzymes
- AST and ALT elevated
70
PCT at an increased risk for these liver disorders
- cirrhosis
| - hepatocellular carcinoma
71
PCT diagnosis
- screening test
| - confirmatory testing
72
PCT screening test tests for
- total plasma porphyrin levels
73
PCT ALA and PBG levels
- normal
| - ALAS1 not induced
74
PCT confirmatory testing tests for
- more specific levels of urinary porphyrins to speciate the porphyria
75
PCT treatment
- remove offending agents
- cover sun exposed areas
- start phlebotomy
76
offending agents of PCT
- no alcohol
- withhold estrogen
- stop smoking
77
what does phlebotomy for PCT do?
- removes iron sequentially
78
lead poisoning - blood levels in adults
> 10 mcg/dL
79
lead poisoning - blood levels in children
> 5 mcg/dL
80
level of safe lead in children?
- no level!
81
sources of lead for adults
- leaded gasoline
- lead paint
- moonshine
- workplace exposures
- mining
- firing ranges
82
sources of lead in children
- prenantal exposure
| - ingestion
83
some ingestion sources of lead in children
- paint
- water
- food
- soil
84
primary source of lead exposure in children
- lead-containing dust
85
lead in drinking water compared to lead in food
- absorbed more than lead in food
86
major route of lead toxicity in adults
- inhalation
87
major route of lead toxicity in children
- ingestion
88
when is lead released from the bone?
- high bone turnover
89
examples of high bone turnover
- pregnancy
- hyperthyroidism
- menopause
- breast feeding
90
lead's biochemical and cellular effects
- inhibits sulfhydryl groups in RBC enzymes ALAS and ferrochelatase in the heme synthetic pathway
91
blockage of pyrimidine 5' nucleotidase causes
- degradation of ribosomal RNA in red blood cells
| - leads to basophilic stippling
92
basophilic stippling associated with
- RNA instability
93
acute effects of lead toxicity
- GI
- anemia
- neurologic
- muscle and joint pain
- lead line
94
GI effects of lead toxicity
- lead colic - crampy abdominal pain
95
type of anemia in lead toxicity
- microcytic
96
classic neurological finding in lead toxicity
- wrist and foot drop
97
what is lead line?
- classic finding of bluish discoloration of the gums
| - lead reacts with plague at the gumline
98
neuropsychiatric effects of chronic lead exposure
- declines in neurocognitive function
- psychiatric symptoms
- distal sensory and motor neuropathy
- EKG conduction delay
- decreased hearing acuity
99
lead nephropathy
- increased hypertension and gout
| - saturnine gout
100
diagnosing lead toxicity
- blood lead levels
| - FEP and ZPP levels
101
blood lead levels
- key clinical monitoring test for diagnosing lead toxicity
102
what kind of stick for blood lead levels
- venous stick
103
FEP and ZPP levels
- indicator of lead exposure and effect over previous 3 month period
104
if FEP and ZPP levels are elevated
- do CBC
| - renal function testing
105
management of lead toxicity
- reduce lead exposure
| - chelation therapy
106
when should chelation be undertaken
- only when exposure has been definitively curtailed
107
bad use of chelation
- use could result in enhanced absorption of lead and worsening toxicity
